Sephin1

Protein phosphatase 1C (PP1c) dephosphorylates the eukaryotic translation initiation factor 2α subunit (eIF2α) to turn off the unfolded protein response in the endoplasmic reticulum (ER). PP1c removes phosphates on eIF2α under the direction of one of two accessory subunits termed protein phosphatase 1 regulatory subunit 15A and 15B (PPP1R15A and PPP1R15B). Whereas PPP1R15B is constitutively expressed, PPP1R15A is induced by protein-misfolding stress. Sephin1 is a selective inhibitor of the stress-induced PPP1R15A that does not affect the constitutive PPP1R15B.¹ At 50 µM, it has been shown to prolong eIF2α phosphorylation after ER stress, delaying translation which protects cells from misfolded protein-induced cytotoxicity.¹ At 1-5 mg/kg, sephin1 has been shown to prevent defects resulting from protein misfolding in a mutant SOD1 mouse model of fast-progressing amyotrophic lateral sclerosis as well as a mouse model of Charcot-Marie-Tooth neuropathy.¹

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1. Das, I., Krzyzosiak, A., Schneider, K., et al. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 348(6231), 239-242 (2015).